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研究生:陳浩元
研究生(外文):Hao Yuan Chen
論文名稱:探討Dtx2在斑馬魚脊髓再生中扮演的角色
論文名稱(外文):The role of Dtx2 in zebrafish spinal cord regeneration
指導教授:鄭邑荃
指導教授(外文):Y. C. Cheng
口試委員:吳嘉霖鄭邑荃皮海薇黃盈誠林正勇
口試委員(外文):C. L. WuY. C. ChengH. W. PiY. C. HuangC. Y. Lin
口試日期:2023-07-21
學位類別:博士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:英文
論文頁數:99
中文關鍵詞:神經幹細胞神經再生管膜輻射狀膠細胞脊髓損傷斑馬魚
外文關鍵詞:Dtx2ependymoradial glianeural regenerationNotchspinal cord injuryzebrafish
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中文摘要 i
Abstract ii
Table of Contents iii
List of figures viii
List of tables x
1. Introduction 1
1.1. Spinal cord regeneration in zebrafish. 1
1.2. Notch signaling 4
1.3. Notch signaling in spinal cord regeneration. 5
1.4. Deltex (Dtx) family 6
2. Material and methods 8
3. Results 17
3.1. Establish a zebrafish model for neural regeneration after spinal cord injury. 17
3.2. Loss of dtx2 enhances spinal cord recovery by accelerating regeneration in zebrafish. 17
3.3. The expression of dtx2 and neural markers during spinal cord regeneration. 18
3.4. dtx2 is expressed in neural stem cells and radial glia in the ependymal layer. 19
3.5. dtx2 mutants alter the gene expression of neural and glial derivatives. 20
3.6. There is more ependymoradial glia in the lesioned spinal cord in dtx2 mutants. 21
3.7. dtx2 mutants have more ependymoradial glia in the spinal cord. 23
3.8. There are more motor neurons in the lesioned spinal cord in dtx2 heterozygote mutants. 24
3.9. Dtx2 regulates Notch signaling downstream molecules during regeneration. 24
3.10. DTX2 inhibits the production of Sox2-positive cells by blocking Notch signaling. 26
3.11. DTX2 binds to the Notch1 intracellular domain directly. 27
3.12. DTX2 down-regulates the Notch1 intracellular domain function by direct binding. 29
3.13. DTX2 binds to each other and forms a multimer. 31
4. Discussion 32
4.1. Dtx2 regulates the balance of ependymoradial glia formation and differentiation in zebrafish spinal cord regeneration. 32
4.2. The novel Dtx2-Notch-Rbpj-Her pathway in the regulation of ependymoradial glia in spinal cord regeneration. 32
4.3. Notch has different roles during different time periods, regulated by the temporal expression of regulators during spinal cord regeneration. 34
4.4. Dtx2 may take part in ependymoradial glia activation after spinal cord injury. 35
4.5. Dtx2 multimer and the different phenotypes in dtx2 mutants. 36
4.6. The interaction between Dtx2 and Notch1 intracellular domain. 37
5. References 39
6. Figures and Tables 48
Figure 1. Establishment of the spinal cord injury model in adult zebrafish. 48
Figure 2. Dtx2 mutants demonstrated faster mobility recovery compared to the wild type. 49
Figure 3. Expression of neural markers and Dtx2 during regeneration. 50
Figure 4. Dtx2 was highly expressed in the lesion site at 12 hours post-injury after spinal cord injury. 52
Figure 5. The signal of Dtx2 was colocalized with Pax6 and Sox2 double-positive cells. 53
Figure 6. Gene expression analysis in the injured spinal cord of dtx2 mutants at 1 day post-injury. 55
Figure 7. Sox2-positive cells increased at the lesion and posterior adjacent sites in dtx2 mutants at 1 day post-injury. 57
Figure 8. Down-regulation of dtx2 did not demonstrate an alteration in the ratio of Sox2-positive cells in the spinal cord at 1 day post-injury. 59
Figure 9. There was no proliferation signal in the 1 day post-injury spinal cord. 60
Figure 10. No alteration in Sox2 positive cells in dtx2 mutants at 3 days post-injury. 61
Figure 11. There is more stemness RG cells in the spinal cord of dtx2 mutant embryos. 63
Figure 12. The number of motor neurons was significantly increased in heterozygous mutants at 7 days post-injury. 64
Figure 13. The Notch downstream genes were up-regulated in the spinal cord of dtx2 mutants at 1 day post-injury. 66
Figure 14. Notch inhibition rescues the reduction of neural stem cells in dtx2 mutants. 67
Figure 15. DTX2 is co-localized with NOTCH1 intracellular domain in the cell nucleus. 69
Figure 16. DTX2 binds to NOTCH1 intracellular domain directly. 70
Figure 17. Dtx2/DTX2 overexpression causes Notch1/NOTCH1 intracellular domain degradation. 71
Figure 18. DTX2 promotes NOTCH1 intracellular domain reduction, not through proteasome or autophagosome degradation. 73
Figure 19. DTX2 promotes NOTCH1 intracellular domain reduction, not through binding to the nucleotides of NOTCH1 intracellular domain. 75
Figure 20. DTX2 will not promote the reduction of NOTCH1 intracellular domain but affect NOTCH1 intracellular domain function by direct binding. 77
Figure 21. DTX2 overexpression reduces the expression of Notch downstream genes. 79
Figure 22. DTX2 binds directly to another DTX2 protein. 80
Figure 23. Working model of the current study. 81
Table 1. 83

List of figures
Figure 1. Establishment of the spinal cord injury model in adult zebrafish.
...................- 48 -
Figure 2. Dtx2 mutants demonstrated faster mobility recovery compared
to the wild type........- 49 -
Figure 3. Expression of neural markers and Dtx2 during regeneration.- 50
-
Figure 4. Dtx2 was highly expressed in the lesion site at 12 hours postinjury after spinal cord injury. ............- 52 -
Figure 5. The signal of Dtx2 was colocalized with Pax6 and Sox2 doublepositive cells............- 53 -
Figure 6. Gene expression analysis in the injured spinal cord of dtx2
mutants at 1 day post-injury................- 55 -
Figure 7. Sox2-positive cells increased at the lesion and posterior
adjacent sites in dtx2 mutants at 1 day post-injury.........- 57 -
Figure 8. Down-regulation of dtx2 did not demonstrate an alteration in the
ratio of Sox2-positive cells in the spinal cord at 1 day post-injury.- 59
-
Figure 9. There was no proliferation signal in the 1 day post-injury spinal
cord............- 60 -
Figure 10. No alteration in Sox2 positive cells in dtx2 mutants at 3 days
post-injury. ..............- 61 -
Figure 11. There is more stemness RG cells in the spinal cord of dtx2
mutant embryos.......- 63 -
Figure 12. The number of motor neurons was significantly increased in
heterozygous mutants at 7 days post-injury......- 64 -
Figure 13. The Notch downstream genes were up-regulated in the spinal
cord of dtx2 mutants at 1 day post-injury. ........- 66 -
Figure 14. Notch inhibition rescues the reduction of neural stem cells in
dtx2 mutants. ...........- 67 -
Figure 15. DTX2 is co-localized with NOTCH1 intracellular domain in
the cell nucleus........- 69 -
Figure 16. DTX2 binds to NOTCH1 intracellular domain directly. ...- 70 -
Figure 17. Dtx2/DTX2 overexpression causes Notch1/NOTCH1
intracellular domain degradation. .......- 71 -
Figure 18. DTX2 promotes NOTCH1 intracellular domain reduction, not
through proteasome or autophagosome degradation. .....- 73 -
Figure 19. DTX2 promotes NOTCH1 intracellular domain reduction, not
through binding to the nucleotides of NOTCH1 intracellular domain.-
75 -
Figure 20. DTX2 will not promote the reduction of NOTCH1
intracellular domain but affect NOTCH1 intracellular domain
function by direct binding.....- 77 -
Figure 21. DTX2 overexpression reduces the expression of Notch
downstream genes.................- 79 -
Figure 22. DTX2 binds directly to another DTX2 protein....- 80 -
Figure 23. Working model of the current study. .....- 81 -

List of tables
Table 1.............- 83 -
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